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Case

63 year old male with 50-pack year smoking history presents with worsening SOB and weight loss

CXR shows central lung lesion, EBUS is performed and biopsy shows small-cell lung cancer

MRI brain and PET/CT performed and multiple lung and liver lesions visualized

Patient started on carboplatin/etoposide/durvalumab with improvement in symptoms

3 months intro treatment, patient suddenly develops worsening SOB after initial improvement

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Q1:

CT shows bilateral ground glass opacities and infiltrates, which of the following is now not on the differential diagnosis for this patient’s shortness of breath?

A. COVID-19
B. Lymphangitic spread of cancer
C. Pulmonary embolism
D. Immune pneumonitis

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Pneumonitis: Definitions

Pneumonitis- Focal or diffuse inflammation of lung parenchyma
Grade

Grade 1 pneumonitis- asymptomatic, found on imaging
Grade 2 pneumonitis- symptomatic
Grade 3 pneumonitis- supplemental oxygen needed
Grade 4 pneumonitis- ventilatory support

Causes:

Chemotherapy- bleomycin, gemcitabine, docetaxel
Targeted therapy- EGFR inhibitors, mTOR inhibitors
Radiation pneumonitis
Immune-mediated- i.e. immune checkpoint inhibitor (anti-PD-1/PD-L1 related)

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_{Histologic patterns of pneumonitis associated with anti–programmed death-1/programmed death ligand 1 therapy on lung biopsy (hematoxylin and eosin [HE] stain magnification, ×200) included (A) cellular interstitial pneumonitis (mild case shown), (B) organizing pneumonia, and (C) diffuse alveolar damage. Additional findings (HE stain magnification, ×400) include (D) poorly formed granulomas, and (E) eosinophils (arrows).}

Published in: Jarushka Naidoo; Xuan Wang; Kaitlin M. Woo; Tunc Iyriboz; Darragh Halpenny; Jane Cunningham; Jamie E. Chaft; Neil H. Segal; Margaret K. Callahan; Alexander M. Lesokhin; Jonathan Rosenberg; Martin H. Voss; Charles M. Rudin; Hira Rizvi; Xue Hou; Katherine Rodriguez; Melanie Albano; Ruth-Ann Gordon; Charles Leduc; Natasha Rekhtman; Bianca Harris; Alexander M. Menzies; Alexander D. Guminski; Matteo S. Carlino; Benjamin Y. Kong; Jedd D. Wolchok; Michael A. Postow; Georgina V. Long; Matthew D. Hellmann; Journal of Clinical Oncology 2017 35709-717.

DOI: 10.1200/JCO.2016.68.2005

Gold Standard: Pathologic Findings of Pneumonitis

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Clinical Presentation

Persistent shortness of breath
Dry cough
Low O2 sat (if pulse oximeter available)

Can be associated with other immune-related adverse events (irAE) like colitis, endocrinopathy

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Diagnostic Dilemma�

Rare (2-5%) but potentially fatal side effect

No gold standard diagnostic criteria aside from biopsy

Symptoms hard to distinguish from PE, disease progression, pneumonia, COPD flare, CHF, tamponade, immune myocarditis etc.

Can happen at any time (week 6-24+ as onset)

In patients who received radiation, distinguishing radiation from immune pneumonitis based on field of radiation

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What about post-radiation patients?

Patients receiving consolidation durvalumab after definitive chemoradiation (PACIFIC) may develop pneumonitis

Overall rate of severe pneumonitis relatively low ~3%

Typically overlay radiation plan onto CT showing pneumonitis to get sense of contribution of components

Academic from treatment perspective since management involves steroids with a slow taper

Twitter: @PatelOncology

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_{Fig 1. Time from first dose of anti–programmed death-1/programmed death ligand 1 therapy to date of pneumonitis event stratified by grade, with interquartile range and median values shown.}

Published in: Jarushka Naidoo; Xuan Wang; Kaitlin M. Woo; Tunc Iyriboz; Darragh Halpenny; Jane Cunningham; Jamie E. Chaft; Neil H. Segal; Margaret K. Callahan; Alexander M. Lesokhin; Jonathan Rosenberg; Martin H. Voss; Charles M. Rudin; Hira Rizvi; Xue Hou; Katherine Rodriguez; Melanie Albano; Ruth-Ann Gordon; Charles Leduc; Natasha Rekhtman; Bianca Harris; Alexander M. Menzies; Alexander D. Guminski; Matteo S. Carlino; Benjamin Y. Kong; Jedd D. Wolchok; Michael A. Postow; Georgina V. Long; Matthew D. Hellmann; Journal of Clinical Oncology 2017 35709-717.

DOI: 10.1200/JCO.2016.68.2005

Time from First Dose of Anti-PD-1: Variable Time to Developing Pneumonitis

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Workup Tips

Disproportionate hypoxia relative to baseline and overall clinical condition

Rapid clinical decline in some patients

CT chest with contrast to rule out PE, PNA, pneumonitis, tamponade, progression

For symptomatic patients, can empirically give steroids+antibiotics while working up

Only regret NOT giving steroid

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_{Fig A1. Radiologic severity of pneumonitis associated with anti–programmed death-1/programmed death ligand 1 therapy stratified into mild, moderate, and severe. CT, computed tomography.}

Published in: Jarushka Naidoo; Xuan Wang; Kaitlin M. Woo; Tunc Iyriboz; Darragh Halpenny; Jane Cunningham; Jamie E. Chaft; Neil H. Segal; Margaret K. Callahan; Alexander M. Lesokhin; Jonathan Rosenberg; Martin H. Voss; Charles M. Rudin; Hira Rizvi; Xue Hou; Katherine Rodriguez; Melanie Albano; Ruth-Ann Gordon; Charles Leduc; Natasha Rekhtman; Bianca Harris; Alexander M. Menzies; Alexander D. Guminski; Matteo S. Carlino; Benjamin Y. Kong; Jedd D. Wolchok; Michael A. Postow; Georgina V. Long; Matthew D. Hellmann; Journal of Clinical Oncology 2017 35709-717.

DOI: 10.1200/JCO.2016.68.2005

Radiographic Severity

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Management

Manage while diagnosing

For highly symptomatic patients consider steroids and antibiotics while CT pending
Prednisone 1mg/kg oral daily

Taper slowly, I typically taper over 4-6 weeks depending on severity

CT chest with contrast
Admission to ICU or high acuity unit for close monitoring
Consider bronchoscopy (BAL to rule out infection)

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Q2: What is your preferred immunosuppression for steroid-refractory immune pneumonitis?

IVIG
Infliximab
Mycophenolate
Cyclophosphamide
Tocilizumab

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Steroid-Refractory Immune Pneumonitis

Steroid-progressive cases (worsening symptoms on steroids)

OR

Steroid-refractory cases (no improvement in 24-48 hours)

High risk population for potentially fatal pneumonitis
No strong data
Higher dose steroids (i.e. methylprednisolone 125mg iv q6hrs) with:

IVIG (400mg/kg/day for 5 days) OR
infliximab 5mg/kg x 1
Case reports on efficacy of mycophenolate, tocilizumab

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Q3: Would you re-challenge a patient with immunotherapy after symptomatic immune-related pneumonitis requiring IVIG and ICU admission?

Yes
No

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Rechallenge after pneumonitis with anti-PD-1?

Default answer is no

Would not try rechallenge with anti-PD-1 if

Severe symptoms (supplemental O2, admission)
Slow or lack of response to steroids

Can consider rechallenge in rare cases with anti-PD-1 if

Asymptomatic (found on imaging alone)
Rapid resolution with steroids
Major clinical benefit and early in treatment
Still very risky, and would not recommend except in rarest of cases

Twitter: @PatelOncology

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Prevention Is The Best Treatment

Higher incidence of pneumonitis after treatment with EGFR TKI, especially osimertinib

15-25% incidence of high-grade pneumonitis with osimertinib after anti-PD-(L)1
Can occur rapidly after starting EGFRi, often within first month
Potential washout from prior aPD1 may be 12mo (or at least 3mo)
Paradoxically may be lower with 1^st gen TKI

So prevention key

Do not treat before getting EGFR result (ideally broader panel)

May be reason to start widespread testing in stage III setting for PACIFIC candidates

Do not let positive high PD-L1 score >50% lead you to start pembro or chemoIO before having a patient’s EGFR status, at very least in your rare/never smokers

Oncogenic EGFR-driven PD-L1 expression is red herring, don’t be fooled by it
Often quite high PD-L1 score in rare/never smoker, but if you look closer, no T cells there so aPD1 wont work but will hurt

If you need to treat for visceral crisis, in never/rare smokers consider chemo (carbo/pem) alone and then add pembro with cycle 2 once NGS back

Schoenfeld et al. Annals of Oncology 2019

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Summary

Immune-related pneumonitis should be considered in all patients receiving immune checkpoint blockade who develop SOB, cough
CT chest with contrast needed given broad differential

Multilobar involvement
Consider troponin and EKG as immune-mediated myocarditis on differential

I prefer to treat while workup pending (prednisone + antibiotic)

Only regret not starting steroids sooner
Taper steroids slowly (4-6 weeks depending on severity)
Symptomatic or steroid-progressive/refractory patients need to be in monitored unit

In steroid-refractory cases can raise dose of steroids (iv methylprednisolone) and add IVIG or infliximab
Rechallenge with immune checkpoint inhibitor is exception, not the rule

Twitter: @PatelOncology

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Thank you

Sandip Patel, MD

Email: patel@ucsd.edu

Twitter: @PatelOncology

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